RU2182905C2 - Derivatives of oxadiazole - Google Patents

Abstract

FIELD: organic chemistry, heterocyclic compounds, pharmacy. SUBSTANCE: invention relates to novel derivatives of oxadiazole of the general formula (I)

where X and Y mean oxygen or nitrogen atom being X and Y can not be oxygen or nitrogen simultaneously; Z means radical of the formula (II)

;

means phenyl radical that can be substituted directly or through alkylene bridges with number of carbon atoms from 1 to 4 by two- fold or threefold with one or some substituents taken among the order: halogen atom, R¹-alkyl, C₁-C₄. Derivatives of oxadiazole of the general formula (I) can be used as drugs in neurodegenerative diseases and brain ischemia of different genesis: epilepsy, CF₃-NR⁵R⁶,NO₂,-OR⁷, hypoxia, anoxia, brain trauma, brain edema, amyotropic lateral sclerosis, Huntington chorea, Alzheimers's disease. EFFECT: new compounds indicated above, valuable medicinal properties. 8 cl, 6 tbl, 10 ex _

Description

 The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to derivatives of oxadiazole.

 Derivatives of oxadiazole with activity, neuroprotective action are known (see application EP-A-504574).

 The objective of the invention is to expand the arsenal of oxadiazole derivatives having a neuroprotective effect.

в которой Х и Y означают кислород или азот, причем Х и Y не могут быть одновременно кислородом или азотом;
Z означает радикал формулы

в которых S¹ и S² означают радикалы формулы

в которых V означает кислород, серу; В и D означают одинаковые или различные C₁-С₁₀-алкиленовые мостики, которые, соответственно, могут быть однократно или многократно замещены такими заместителями, как =0, 1,3-диоксолан или 1,3-диоксан.The problem is solved by the proposed derivatives of oxadiazole of the general formula (I)

in which X and Y mean oxygen or nitrogen, and X and Y cannot be simultaneously oxygen or nitrogen;
Z is a radical of the formula

in which S ¹ and S ² mean radicals of the formula

in which V means oxygen, sulfur; B and D mean identical or different C ₁ -C ₁₀ alkylene bridges, which, respectively, can be substituted once or repeatedly by substituents such as = 0, 1,3-dioxolane or 1,3-dioxane.

в которой V и В имеют вышеприведенные значения, a U означает С₃-С₆-циклоалкильную группу или С₆-С₁₀-арильную группу, которые, соответственно, могут быть однократно или многократно замещены С₁-С₄-алкилом, -NR⁵R⁶;
S¹ и S² означают радикалы формулы

в которой В и D имеют вышеприведенные значения и обе группы D и оба радикала R⁴ могут быть одинаковыми или различными;
S¹ и S² означают радикалы формулы

причем V и D имеют вышеприведенные значения;
S¹ и S² означают радикалы формулы

,
причем V и U имеют вышеприведенные значения;
S¹ и S² означают радикалы формулы

причем D имеет вышеприведенные значения и обе группы D и оба радикала R⁴ могут быть одинаковыми или различными;
S¹ и S² означают радикалы формулы

в которых Е означает NR⁷ (n, m=2 или 3 и n+m>2);
S¹ и S² означают радикалы формулы

в которой V и D имеют вышеприведенные значения и W означает радикал формулы

при необходимости замещенный С₁-С₄-алкилом, в которых Е означает NR⁷, a n, m, l=0,1 или 2, или W означает подсоединенный через атом углерода 5, 6-членный гетероцикл, содержащий один или несколько гетероатомов из ряда азот, кислород, который при необходимости может быть замещен бензилом или С₁-С₄-алкилом;
S¹ и S² означают радикалы формулы
-V-W
в которой V и W имеют вышеприведенные значения;
S¹ и S² означают радикалы формулы

в которой В имеет вышеприведенные значения и оба заместителя R⁷ могут быть одинаковыми или различными;
S¹ и S² означают радикалы формулы

в которой оба заместителя R⁷ могут быть одинаковыми или различными;
S³ и S⁴ означают радикалы формулы

в которой В, V и D имеют вышеприведенные значения;
S³ и S⁴ означают радикалы формулы

в которой В и D имеют вышеприведенные значения и обе группы D и оба заместителя R⁴ могут быть как одинаковыми, так и различными;
S³ и S⁴ означают радикалы формулы

в которой V и D имеют вышеприведенные значения;
S³ и S⁴ означают радикалы формулы

в которой D имеет вышеприведенные значения, и обе группы D и оба заместителя R⁴ могут быть как одинаковыми, так и различными;
Q означает конденсированный, однократно ненасыщенный 5-членный цикл, который может содержать один или несколько гетероатомов из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴
в которой D имеет вышеприведенные значения;
R¹ означает фенильный радикал, который при необходимости замещен напрямую или через алкиленовые мостики с числом атомов углерода от 1 до 4 однократно, двухкратно или трехкратно одним или несколькими заместителями из ряда галоген, С₁-С₄-алкил, -CF₃, -NR⁵R⁶, -NO₂, -OR⁷,
или заместителем формулы

в которой В, V или D имеют вышеприведенные значения;
R¹ означает фенил, который замещен заместителем формулы

в которой V и D имеют вышеприведенные значения;
R¹ означает фенил-С₁-С₆-алкил, предпочтительно фенил-С₁-С₄-алкил, фенил-С₂-С₆-алкенил;
R¹ означает радикал формулы М-, причем М - это 5, 6-членный гетероцикл, присоединенный через С- или N-атом, который содержит один гетероатом из ряда азот, кислород или сера;
R¹ означает С₃-С₇-циклоалкильный радикал;
R¹ означает, при необходимости замещенный С₁-С₄-алкилом, предпочтительно метилом, норборнановый, норборненовый радикалы, предпочтительно адамантан или норадамантан радикалы;
R¹ означает при необходимости замещенный радикал формулы

R² и R³ означают одинаковые или различные радикалы такие, как водород, галоген, -OR⁷, C₁-С₁₀-алкил;
R⁴ означает амин формулы -NR⁵R⁶;
R⁴ означает N-оксид формулы

R⁵ означает водород, С₁-С₁₀-алкил;
R⁶ означает водород, C₁-С₁₀-алкил;
R⁶ означает С₆-С₁₀-арил, предпочтительно фенил;
R⁷ означает водород, С₁-С₄-алкил;
при необходимости, в форме их рацематов, их энантиомеров, в форме их диастереомеров или их смесей, а также, при необходимости, их фармакологически безопасных солей с кислотами.S ¹ and S ² mean radicals of the formula

in which V and B have the above meanings, a U means a C ₃ -C ₆ cycloalkyl group or a C ₆ -C ₁₀ aryl group, which, respectively, can be substituted once or repeatedly by C ₁ -C ₄ alkyl, -NR ⁵ R ⁶ ;
S ¹ and S ² mean radicals of the formula

in which B and D have the above meanings and both groups D and both radicals R ⁴ may be the same or different;
S ¹ and S ² mean radicals of the formula

wherein V and D have the above meanings;
S ¹ and S ² mean radicals of the formula

,
wherein V and U have the above meanings;
S ¹ and S ² mean radicals of the formula

moreover, D has the above meanings and both groups D and both radicals R ⁴ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which E means NR ⁷ (n, m = 2 or 3 and n + m>2);
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings and W means a radical of the formula

optionally substituted with C ₁ -C ₄ alkyl, in which E is NR ⁷ , an, m, l = 0.1 or 2, or W is a 5, 6-membered heterocycle connected via a carbon atom containing one or more heteroatoms from a number of nitrogen, oxygen, which, if necessary, can be replaced by benzyl or C ₁ -C ₄ -alkyl;
S ¹ and S ² mean radicals of the formula
-VW
in which V and W have the above meanings;
S ¹ and S ² mean radicals of the formula

in which B has the above meanings and both substituents R ⁷ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which both substituents R ⁷ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which B, V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which B and D have the above meanings and both groups D and both substituents R ⁴ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which D has the above meanings, and both groups D and both substituents R ⁴ may be the same or different;
Q means a condensed, once unsaturated 5-membered ring, which may contain one or more heteroatoms from the series oxygen;
S ⁵ means a radical of the formula
-DR ⁴
in which D has the above meanings;
R ¹ means a phenyl radical which, if necessary, is substituted directly or via alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C ₁ -C ₄ alkyl, -CF ₃ , -NR ⁵ R ⁶ , -NO ₂ , -OR ⁷ ,
or a substituent of the formula

in which B, V or D have the above meanings;
R ¹ means phenyl, which is substituted by a substituent of the formula

in which V and D have the above meanings;
R ¹ is phenyl-C ₁ -C ₆ -alkyl, preferably phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₆ -alkenyl;
R ¹ means a radical of the formula M—, wherein M is a 5, 6-membered heterocycle attached via a C- or N-atom which contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ is a C ₃ -C ₇ cycloalkyl radical;
R ¹ means, optionally substituted with C ₁ -C ₄ -alkyl, preferably methyl, norbornane, norbornene radicals, preferably adamantane or noradamantane radicals;
R ¹ means, if necessary, a substituted radical of the formula

R ² and R ³ mean the same or different radicals such as hydrogen, halogen, —OR ⁷ , C ₁ -C ₁₀ alkyl;
R ⁴ is an amine of the formula —NR ⁵ R ⁶ ;
R ⁴ means an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₁₀ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₁₀ -alkyl;
R ⁶ is C ₆ -C ₁₀ aryl, preferably phenyl;
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl;
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers or their mixtures, and also, if necessary, their pharmacologically safe salts with acids.

в которой Х и Y означают кислород или азот, причем Х и Y не могут быть оба одновременно кислородом или азотом,

Z означает радикал формулы в которой
S¹ и S² означают радикалы формулы

в которой V означает кислород, серу, В и D означают одинаковые или, различные С₁-С₄-алкиленовые мостики, которые могут быть замещены такими заместителями, как =0;
S¹ и S² означают радикалы формулы

в которой V и В имеют вышеприведенное значение, a U означает С₃-С₆-циклоалкильную или С₆-С₁₀-арильную группы, которые могут быть замещены такими заместителями, как С₁-С₄-алкил, -NR⁵R⁶;
S¹ и S² означают радикалы формулы

в которой В и D имеют вышеприведенные значения и обе группы D, а также оба радикала R⁴ могут быть как одинаковыми, так и различными;
S¹ и S² означают радикалы формулы

в которой V и D имеют вышеприведенные значения;
S¹ и S² означают радикалы формулы

в которой V и U имеют вышеприведенные значения
S¹ и S² означают радикалы формулы

в которой D имеет вышеприведенное значение и обе группы D, а также оба радикала R⁴ могут быть как одинаковыми, так и различными;
S¹ и S² означают радикалы формулы

в которой Е означает NR⁷ (n, m=2 или 3 и n+m>2);
S¹ и S² означают радикалы формулы

в которой V и D имеют вышеприведенные значения, a W означает радикал формулы

при необходимости С₁-С₄-алкилом, в котором Е означает NR⁷, n, m, l=0, 1 или 2, или W означает присоединенный через атом углерода 5, 6-членный гетероцикл, содержащий один или несколько гетероатомов из ряда азот, кислород, который, при необходимости, может быть замещен бензилом или С₁-С₄-алкилом;
S¹ и S² означают радикалы формулы
-V-W
в которых V и W имеют вышеприведенные значения;
S¹ и S² означают радикалы формулы

в которой В имеет вышеприведенные значения и заместители R⁷ могут быть как одинаковыми, так и различными;
S¹ и S² означают радикалы формулы

в которой заместители R⁷ могут быть как одинаковыми, так и различными;
S³ и S⁴ означают радикалы формулы

в которой В, V и D имеют вышеприведенные значения;
S³ и S⁴ означают радикалы формулы

в которой В и D имеют вышеприведенные значения и обе группы D, а также оба заместителя R⁴ могут быть как одинаковыми, так и различными;
S³ и S⁴ означают радикалы формулы

в которой V и D имеют вышеприведенные значения;
S³ и S⁴ означают радикалы формулы

в которой D имеет вышеприведенные значения и обе группы D, а также оба заместителя R⁴ могут быть одинаковыми или различными;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, содержащий один или несколько гетероатомов из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴,
в которой D имеет вышеприведенные значения;
R¹ означает фенильный радикал, который при необходимости однократно или многократно замещен одним или несколькими заместителями такими, как галоген, предпочтительно фтор, хлор или бром, С₁-С₄-алкильный радикал, -СF₃, -NR⁵R⁶, -NO₂, -OR⁷ или одним радикалом формулы

в которой В, V и D имеют вышеприведенные значения;
R¹ означает фенильный радикал, который может быть замещен заместителем формулы

в которой В, V и U имеют вышеприведенные значения;
R¹ означает фенильный радикал, который замещен заместителем формулы

в которой V и D имеют вышеприведенные значения;
R¹ означает фенил-С₁-С₄-алкил, предпочтительно бензил, фенил-С₂-С₄-алкенил;
R¹ означает радикал формулы М-, причем М - это 5 или 6-членный гетероцикл, присоединенный через С- или N-атом, который содержит один гетероатом из ряда азот, кислород или сера;
R¹ означает С₃-С₇-циклоалкил, предпочтительно циклопропил или циклопентил;
R¹ означает, при необходимости замещенный С₁-С₄-алкилом предпочтительно метилом, норборнан-, норборнен-радикалы, предпочтительно адамантан- или норадамантан-радикалы;
R¹ означает, при необходимости однократно или многократно замещенный галогеном, гидроксигруппой или метоксигруппой радикал формулы

R² и R³ означают одинаковые или различные радикалы такие, как водород, гидроксигруппа, галоген, предпочтительно фтор, хлор или бром, С₁-С₄-алкилоксигруппа, предпочтительно метилоксигруппа, С₁-С₄-алкил;
R⁴ означает -NR⁵R⁶,
R⁴ означает N-оксид с формулой

R⁵ означает водород, C₁-C₄-алкил,
R⁶ означает водород, С₁-С₄-алкил;
R⁶ означает фенильный радикал,
R⁷ означает водород, С₁-С₄-алкил;
при необходимости в форме их рацематов, их энантиомеров, в форме их диастереомеров и их смесей, а также, при необходимости, их фармакологически безопасных солей с кислотами.Compounds of general formula (I) are preferred

in which X and Y mean oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen,

Z is a radical of the formula in which
S ¹ and S ² mean radicals of the formula

in which V is oxygen, sulfur, B and D are the same or different C ₁ -C ₄ alkylene bridges which may be substituted with substituents such as = 0;
S ¹ and S ² mean radicals of the formula

in which V and B are as defined above, a U is a C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₀ aryl group which may be substituted with substituents such as C ₁ -C ₄ alkyl, -NR ⁵ R ⁶ ;
S ¹ and S ² mean radicals of the formula

in which B and D have the above meanings and both groups D, as well as both radicals R ⁴ can be the same or different;
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings;
S ¹ and S ² mean radicals of the formula

in which V and U have the above meanings
S ¹ and S ² mean radicals of the formula

in which D has the above meaning and both groups D, as well as both radicals R ⁴ can be the same or different;
S ¹ and S ² mean radicals of the formula

in which E means NR ⁷ (n, m = 2 or 3 and n + m>2);
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings, and W means a radical of the formula

optionally C ₁ -C ₄ -alkyl in which E is NR ⁷ , n, m, l = 0, 1 or 2, or W is a 5, 6-membered heterocycle attached via a carbon atom containing one or more hetero atoms from the series nitrogen, oxygen, which, if necessary, may be substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ and S ² mean radicals of the formula
-VW
in which V and W have the above meanings;
S ¹ and S ² mean radicals of the formula

in which B has the above meanings and the substituents R ⁷ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which the substituents R ⁷ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which B, V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which B and D have the above meanings and both groups D, as well as both substituents R ⁴ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which D has the above meanings and both groups D, as well as both substituents R ⁴ may be the same or different;
Q means a condensed, once unsaturated 5-membered heterocycle containing one or more oxygen heteroatoms;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical, which, if necessary, is substituted once or repeatedly by one or more substituents, such as halogen, preferably fluorine, chlorine or bromine, a C ₁ -C ₄ alkyl radical, —CF ₃ , —NR ⁵ R ⁶ , —NO ₂ , -OR ⁷ or one radical of the formula

in which B, V and D have the above meanings;
R ¹ means a phenyl radical which may be substituted with a substituent of the formula

in which B, V and U have the above meanings;
R ¹ means a phenyl radical which is substituted with a substituent of the formula

in which V and D have the above meanings;
R ¹ means phenyl-C ₁ -C ₄ -alkyl, preferably benzyl, phenyl-C ₂ -C ₄ -alkenyl;
R ¹ means a radical of the formula M—, wherein M is a 5 or 6 membered heterocycle attached via a C or N atom which contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ is C ₃ -C ₇ cycloalkyl, preferably cyclopropyl or cyclopentyl;
R ¹ means, optionally substituted with C ₁ -C ₄ alkyl, preferably methyl, norbornane, norbornene radicals, preferably adamantane or noradamantane radicals;
R ¹ means, if necessary, once or repeatedly substituted by a halogen, hydroxy group or methoxy group, a radical of the formula

R ² and R ³ mean the same or different radicals, such as hydrogen, hydroxy group, halogen, preferably fluorine, chlorine or bromine, C ₁ -C ₄ -alkyloxy group, preferably methyloxy, C ₁ -C ₄ -alkyl;
R ⁴ means —NR ⁵ R ⁶ ,
R ⁴ means an N-oxide with the formula

R ⁵ means hydrogen, C ₁ -C ₄ -alkyl,
R ⁶ means hydrogen, C ₁ -C ₄ -alkyl;
R ⁶ means a phenyl radical,
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl;
if necessary in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids.

в которой Х и Y означают кислород или азот, причем Х и Y не могут быть одновременно кислородом или азотом,
Z означает радикал формулы

в которой S¹ означает радикал формулы

в которой V означает кислород, серу и В и D означают одинаковые или различные С₁-С₄-алкиленовые, мостики, которые могут быть замещены такими заместителями, как =0;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения;
S¹ означает радикал формулы

в которой V имеет вышеприведенные значения и U означает С₃-С₆-циклоалкильную или фенильную группы, которые могут быть замещены С₁-С₄-алкилом;
S¹ означает радикал формулы

в которой В и D имеют вышеприведенные значения и обе группы D, а также оба заместителя R⁴ одинаковы или различны;
S¹ означает радикал формулы

в которой D имеет вышеприведенные значения и обе группы D, а также оба заместителя R⁴ одинаковы или различны;
S¹ означает радикал формулы

в которой Е означает NR⁷ (с n, m=2 или 3 и n+m>2);
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения, a W означает радикал формулы

при необходимости замещенный С₁-С₄-алкилом, в которой Е означает NR⁷, n, m, l=0, 1 или 2,
или W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, который содержит один или несколько гетероатомов из ряда азот, кислород и который при необходимости замещен бензилом или С₁-С₄-алкилом;
S¹ означает радикал формулы
-V-W
в которой V и W имеют вышеприведенные значения;
S² означает радикал формулы

в которой V и D имеют вышеприведенные значения;
S⁴ означает радикал формулы

в которой V и D имеют вышеприведенные значения;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, содержащий один или несколько гетероатомов из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴,
в которой D имеет вышеприведенные значения;
R¹ означает бензильный или фенильный радикал, причем последний может быть однократно или многократно замещен одним или несколькими заместителями такими, как фтор, хлор или бром, -С₁-С₄-алкил, -CF₃, -NMe₂,-NEt₂, -NO₂ или -OR⁷;
R¹ означает фенильный радикал, замещенный радикалом формулы

в которой V означает кислород и D означает С₁-С₄-алкильный мостик;
R¹ означает 5- или 6-членный гетероцикл, присоединенный через атом углерода или азота, который содержит один гетероатом из ряда азот, кислород или сера;
R¹ означает циклопропил, цикпопентил или циклогексил;
R¹ означает норборнан, норборнен, адамантан или норадамантан, при необходимости замещенные метальной группой;
R¹ означает радикал формулы

R¹ означает -СН=СН-фенил;
R² означает водород, фтор, хлор, бром, C₁-C₄-алкилоксигруппу, С₁-С₄-алкил или гидроксигруппу;
R³ означает водород;
R⁴ означает -NR⁵R⁶;
R⁴ означает N-оксид формулы

R⁵ означает водород, C₁-С₃-алкил;
R⁶ означает водород, C₁-С₃-алкил, бензил или фенил;
R⁷ означает водород, С₁-С₄-алкил, бензил;
при необходимости, в форме их рацематов, их энантиомеров, в форме стереомеров или их смесей, а также при необходимости, их фармакологически безопасных солей с кислотами.Particularly preferred are oxadiazole derivatives of the general formula (I)

in which X and Y mean oxygen or nitrogen, and X and Y cannot be simultaneously oxygen or nitrogen,
Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur and B and D are the same or different C ₁ -C ₄ alkylene bridges which may be substituted with substituents such as = 0;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means a radical of the formula

in which V has the above meanings and U is C ₃ -C ₆ cycloalkyl or phenyl groups which may be substituted with C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula

in which B and D have the above meanings and both groups D as well as both substituents R ^{4 are the} same or different;
S ¹ means a radical of the formula

in which D has the above meanings and both groups D, as well as both substituents R ^{4 are the} same or different;
S ¹ means a radical of the formula

in which E means NR ⁷ (with n, m = 2 or 3 and n + m>2);
S ¹ means a radical of the formula

in which V and D have the above meanings, and W means a radical of the formula

optionally substituted with C ₁ -C ₄ alkyl in which E is NR ⁷ , n, m, l = 0, 1 or 2,
or W means a 5- or 6-membered heterocycle attached via a carbon atom that contains one or more heteroatoms from the series nitrogen, oxygen and which is optionally substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula
-VW
in which V and W have the above meanings;
S ² means a radical of the formula

in which V and D have the above meanings;
S ⁴ means a radical of the formula

in which V and D have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle containing one or more oxygen heteroatoms;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a benzyl or phenyl radical, the latter can be singly or repeatedly substituted by one or more substituents such as fluorine, chlorine or bromine, —C ₁ -C ₄ alkyl, —CF ₃ , —NMe ₂ , —NEt ₂ , -NO ₂ or -OR ⁷ ;
R ¹ means a phenyl radical substituted with a radical of the formula

in which V is oxygen and D is a C ₁ -C ₄ alkyl bridge;
R ¹ means a 5- or 6-membered heterocycle attached via a carbon or nitrogen atom that contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ means cyclopropyl, cyclopentyl or cyclohexyl;
R ¹ means norbornane, norbornene, adamantane or noradamantane, optionally substituted with a methyl group;
R ¹ means a radical of the formula

R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁴ means an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl, benzyl;
if necessary, in the form of their racemates, their enantiomers, in the form of stereomers or their mixtures, and also, if necessary, their pharmacologically safe salts with acids.

в которой Х и Y означают кислород или азот, причем Х и Y не могут быть оба одновременно кислородом или азотом;
Z означает радикал формулы

в которой S¹ означает радикал формулы

в которой V означает кислород, серу, В означает -CH₂- и D означает одну из групп -СН₂-, -СН₂-СН₂-, -СН₂-СН₂-СН₂-, -СН₂-С(СН₃)Н-, -СН₂-СО-, -СН₂-СН₂-СО-;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения;
S¹ означает радикалы пиперазин-1-ил, 4-метилпиперазин-1-ил;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения, а
W означает радикал формулы

при необходимости замещенный С₁-С₄-алкильной группой или
W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, содержащий азот, который при необходимости замещен бензилом или C₁-C₄-алкилом;
R¹ означает радикал формулы
-V-W,
в которой V и W имеют вышеприведенные значения
S² означает радикал формулы
-(CH₂)_0,1-O-(CH₂)_2,3-R⁴,
Q означает конденсированный, однократно ненасыщенный 5-членный цикл, который может содержать один гетероатом из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴,
в которой D имеет вышеприведенные значения;
R¹ означает радикалы циклопропил, циклопентил, бензил или фенил, причем последний может быть однократно или многократно замещен одним или несколькими заместителями, такими как фтор, хлор, бром, С₁-С₄-алкил, -CF₃, -NMe₂, -NO₂ или -OR⁷;
R¹ означает фенил, замещенный радикалом формулы
-O-(CH₂)_2,3-R⁴,
R¹ означает фуран, тиофен, пиридин или пиррол;
R¹ означает норборнан, норборнен, адамантан или норадамантан;
R¹ означает -СН=СН-фенил;
R² означает водород, фтор, хлор, бром, С₁-С₄-алкилоксигруппу, С₁-С₄-алкил или гидроксигруппу;
R³ означает водород;
R⁴ означает -NR⁵R⁶ или N-оксид формулы

R⁵ означает водород, C₁-С₃-алкил;
R⁶ означает водород, С₁-С₃-алкил, бензил или фенил;
R⁷ означает водород, метил, этил, пропил, изопропил, бутил, трет-бутил;
при необходимости, в форме их рацематов, их энантиомеров, в форме их диастереомеров и их смесей, а также, при необходимости, их фармакологически безопасных солей с кислотами.Of particular interest are compounds of general formula (I)

wherein X and Y are oxygen or nitrogen, wherein X and Y cannot both be oxygen or nitrogen at the same time;
Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur, B is —CH ₂ - and D is one of —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ —CH ₂ -, —CH ₂ —C ( CH ₃ ) H-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings, and
W means a radical of the formula

optionally substituted with a C ₁ -C ₄ alkyl group or
W is a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which is optionally substituted with benzyl or C ₁ -C ₄ alkyl;
R ¹ means a radical of the formula
-VW,
in which V and W have the above meanings
S ² means a radical of the formula
- (CH ₂ ) _0,1 -O- (CH ₂ ) _2,3 -R ⁴ ,
Q means a condensed, once unsaturated 5-membered ring, which may contain one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means radicals cyclopropyl, cyclopentyl, benzyl or phenyl, the latter can be singly or repeatedly substituted by one or more substituents, such as fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl, -CF ₃ , -NMe ₂ , - NO ₂ or -OR ⁷ ;
R ¹ means phenyl substituted by a radical of the formula
-O- (CH ₂ ) _2,3 -R ⁴ ,
R ¹ means furan, thiophene, pyridine or pyrrole;
R ¹ means norbornane, norbornene, adamantane or noradamantane;
R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
R ⁷ means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl;
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids.

Х и Y означают азот или кислород, причем Х и Y не могут быть одновременно кислородом или азотом,
Z означает радикал формулы

в которой S¹ означает радикал формулы

в которой V означает кислород, серу, В означает -СН₂- и D означает одну изгрупп-CH₂,-CH₂-CH₂-,-СН₂-СН₂-СН₂-,-СН₂-С(СН₃)Н-,-СН₂-СО-,-СН₂-СН₂-СО-;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения;
S¹ означает радикалы пиперазин-1-ил, 4-метилпиперазин-1-ил;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения и W означает радикал с формулой

при необходимости замещенный С₁-С₄-алкильной группой, или W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, содержащий азот, который может быть, при необходимости, замещен бензилом или С₁-С₄-алкилом;
S¹ означает радикал формулы
-V-W,
в которой V и W имеют вышеприведенные значения;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, который содержит один гетероатом из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴,
в которой D имеет вышеприведенные значения;
R¹ означает радикалы циклопропил, циклопентил или фенил, причем фенильный цикл может быть однократно или многократно замещен одним или несколькими заместителями, такими как фтор, хлор, бром, С₁-С₄-алкильный радикал, -СF₃, -NMe₂, -NO₂ или -OR⁷;
R¹ означает фуран, тиофен, пиридин или пиррол;
R¹ означает норборнан, норборнен, адамантан или норадамантан;
R¹ означает -СН=СН-фенил;
R² означает водород, фтор, хлор, бром, С₁-С₄-алкилоксигруппу, С₁-С₄-алкил или гидроксигруппу;
R³ означает водород;
R⁴ означает, -NR⁵R⁶ или N-оксид формулы

в которой R⁵ означает водород, С₁-С₃-алкил;
R⁶ означает водород, С₁-С₃-алкил, бензил или фенил;
при необходимости, в форме их рацематов, их энантиомеров, в форме их диастереомеров и их смесей, а также, при необходимости, их фармакологически безопасных солей с кислотами.Of particular interest are the compounds of general formula (I) in which

X and Y mean nitrogen or oxygen, wherein X and Y cannot simultaneously be oxygen or nitrogen,
Z is a radical of the formula

in which S ¹ means a radical of the formula

wherein V is oxygen, sulfur, B is -CH ₂ - and D represents one izgrupp-CH _2, -CH ₂ -CH ₂ -, - CH ₂ -CH ₂ -CH ₂ -, - CH ₂ -C (CH ₃ ) H -, - CH ₂ -CO -, - CH ₂ -CH ₂ -CO-;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings and W means a radical with the formula

optionally substituted with a C ₁ -C ₄ alkyl group, or W means a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which may optionally be substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle that contains one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means radicals cyclopropyl, cyclopentyl or phenyl, and the phenyl ring may be substituted once or repeatedly by one or more substituents, such as fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl radical, -CF ₃ , -NMe ₂ , - NO ₂ or -OR ⁷ ;
R ¹ means furan, thiophene, pyridine or pyrrole;
R ¹ means norbornane, norbornene, adamantane or noradamantane;
R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

in which R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids.

в которой Х и Y означает кислород или азот, причем Х и Y не могут быть оба одновременно кислородом или азотом;
Z означает радикал формулы

в которой S¹ означает радикал формулы

в которой V означает кислород, серу и D означает одну из групп -CH₂-, -СН₂-СН₂-, -СН₂-СН₂-СН₂-, -СН₂-С(СН₃)Н-,-СН₂-СО-, -СН₂-СН₂-СО-;
S¹ означает радикалы пиперазин-1-ил, 4-метилпиперазин-1-ил;
S¹ означает радикал формулы

в которой V и D имеют вышеприведенные значения и W означает радикал формулы

или W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, содержащий азот, который при необходимости, замещен метильной группой;
S¹ означает радикал формулы
-V-W,
в которой V и W имеют вышеприведенные значения;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, который содержит один гетероатом из ряда кислород;
S⁵ означает радикал формулы
-D-R⁴,
в которой D имеет вышеприведенные значения;
R¹ означает фенильный радикал, который при необходимости, однократно или многократно замещен одним или несколькими заместителями такими, как фтор, хлор, бром, метил, этил, н-пропил, изопропил, н-бутил, трет-бутил, -CF₃ или -OR⁷;
R¹ означает фуран, тиофен или пиридин;
R² означает водород, фтор, хлор, бром, метил, метилоксигруппу или гидроксигруппу;
R³ означает водород;
R⁴ означает -NR⁵R⁶ или N-оксид с формулой

R⁵ означает водород, метил, этил, н-пропил, изопропил;
R⁶ означает водород, метил, этил, н-пропил, изопропил, бензил или фенил;
R⁷ означает водород, метил или этил;
при необходимости, в форме их рацематов, их энантиомеров, в форме их диастереомеров и их смесей, при необходимости, их фармакологически безопасных солей с кислотами.Further, of great interest are compounds of general formula (I)

wherein X and Y are oxygen or nitrogen, wherein X and Y cannot both be oxygen or nitrogen at the same time;
Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur and D is one of the groups —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ —CH ₂ -, —CH ₂ —C (CH ₃ ) H -, - CH ₂ —CO—, —CH ₂ —CH ₂ —CO—;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings and W means a radical of the formula

or W means a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which is optionally substituted with a methyl group;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle that contains one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical which, if necessary, is substituted once or repeatedly by one or more substituents, such as fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF ₃ or - OR ⁷ ;
R ¹ means furan, thiophene or pyridine;
R ² is hydrogen, fluoro, chloro, bromo, methyl, methyloxy or hydroxy;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

R ⁵ means hydrogen, methyl, ethyl, n-propyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;
R ⁷ means hydrogen, methyl or ethyl;
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if necessary, their pharmacologically safe salts with acids.

в которой Х и Y означают кислород или азот, причем Х и Y не могут быть одновременно кислородом или азотом;
Z означает радикал формулы,

в которой S¹ означает радикал формулы

в которой V означает кислород и D означает одну из групп -CH₂-, -CH₂-CH₂-, -СН₂-С(СН₃)Н-,-СН₂-СН₂-СО-;
S¹ означает радикалы N-пиперазинил;
S¹ означает радикал формул

в которой V и D имеют вышеприведенные значения, a W означает радикал формулы

или W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, содержащий азот, при необходимости замещенный метильной группой;
S¹ означает радикал формулы
-V-W,
в которой V и W имеют вышеприведенные значения;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, содержащий в качестве гетероатома кислород;
S⁵ означает радикал формулы
-D-R⁴,
в котором D имеет вышеприведенные значения;
R¹ означает фенильный радикал, который может быть однократно или многократно замещен одним или несколькими заместителями такими, как фтор, хлор, бром, метильный радикал, -СF₃, гидроксигруппа, метилоксигруппа или этилоксигруппа;
R¹ означает фуран, тиофен или пиридин;
R² означает водород, фтор, хлор или метил;
R³ означает водород;
R⁴ означает -NR⁵R⁶;
R⁵ означает водород, метил, этил, н-пропил, изопропил;
R⁶ означает водород, метил, этил, н-пропил, изопропил, бензил или фенил;
при необходимости в форме их рацематов, их энантиомеров, в форме их диастереомеров и их смесей, при необходимости, их фармакологически безопасных солей с кислотами.Of particular importance are the compounds of general formula (I)

in which X and Y mean oxygen or nitrogen, and X and Y cannot be simultaneously oxygen or nitrogen;
Z is a radical of the formula

in which S ¹ means a radical of the formula

wherein V denotes oxygen and D is one of the groups -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -C (CH ₃₎ H -, - CH ₂ -CH ₂ -CO-;
S ¹ means the radicals of N-piperazinyl;
S ¹ means a radical of the formulas

in which V and D have the above meanings, and W means a radical of the formula

or W is a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, optionally substituted with a methyl group;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle containing oxygen as a heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical which may be substituted once or repeatedly by one or more substituents such as fluorine, chlorine, bromine, methyl radical, —CF ₃ , hydroxy group, methyloxy group or ethyloxy group;
R ¹ means furan, thiophene or pyridine;
R ² means hydrogen, fluorine, chlorine or methyl;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁵ means hydrogen, methyl, ethyl, n-propyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;
if necessary in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if necessary, their pharmacologically safe salts with acids.

в которой
Х и Y означают кислород или азот, причем Х и Y не могут быть одновременно кислородом или азотом;
Z означает радикал формулы

в которой S¹ означает один из радикалов -O-CH₂-CH₂-R⁴, -O-СН₂-С(СН₃)Н-R⁴, -O-С(СН₃)Н-CH₂-R⁴ или -CH₂-CH₂-CO-R⁴;
S¹ означает один из радикалов -O-CH₂-W или -O-W, в которых W означает присоединенный через атом углерода 5- или 6-членный гетероцикл, включающий атом азота, который, при необходимости, замещен метильной группой;
Q означает конденсированный, однократно ненасыщенный 5-членный гетероцикл, содержащий в качестве гетероатома кислород;
S⁵ означает радикал формулы -CH-R⁴;
R¹ означает фенильный радикал, который может быть однократно или многократно замещен одним или несколькими заместителями такими, как фтор, хлор, бром, метил, -СF₃, гидроксигруппа, метилоксигруппа или этилоксигруппа;
R¹ означает тиофен;
R² означает водород, фтор, хлор или метил;
R³ означает водород;
R⁴ означает -NR⁵R⁶;
R⁵ означает водород, метил, этил, изопропил;
R⁶ означает водород, метил, этил, изопропил, бензил или фенил;
при необходимости в форме их рацематов, их энантиомеров, в форме их диастереомеров или их смесей; при необходимости, их фармакологически безопасных солей с кислотами.Compounds of general formula (I) are particularly preferred according to the invention

wherein
X and Y are oxygen or nitrogen, wherein X and Y cannot be simultaneously oxygen or nitrogen;
Z is a radical of the formula

in which S ¹ means one of the radicals —O — CH ₂ —CH ₂ —R ⁴ , —O — CH ₂ —C (CH ₃ ) H — R ⁴ , —O — C (CH ₃ ) H — CH ₂ —R ⁴ or -CH ₂ -CH ₂ -CO-R ⁴ ;
S ¹ means one of the radicals —O — CH ₂ —W or —OW, in which W is a 5- or 6-membered heterocycle attached via a carbon atom, including a nitrogen atom, which is optionally substituted with a methyl group;
Q means a condensed, once unsaturated 5-membered heterocycle containing oxygen as a heteroatom;
S ⁵ means a radical of the formula —CH — R ⁴ ;
R ¹ means a phenyl radical which may be substituted once or repeatedly by one or more substituents such as fluorine, chlorine, bromine, methyl, —CF ₃ , hydroxy, methyloxy or ethyloxy;
R ¹ means thiophene;
R ² means hydrogen, fluorine, chlorine or methyl;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁵ means hydrogen, methyl, ethyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl;
if necessary in the form of their racemates, their enantiomers, in the form of their diastereomers or their mixtures; if necessary, their pharmacologically safe salts with acids.

 By alkyl groups or alkyls (and in the case when they are components of other substituents, for example alkylene bridges), unless otherwise specified, branched or unbranched alkyl groups with carbon atoms from 1 to 10, preferably with carbon atoms from 1 to 4, examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl. To denote methyl, ethyl, butyl or tert-butyl groups, the abbreviations Me, Et, Bu and tBu are also used.

Substituted alkyl groups, unless otherwise specified (and when they are components of other substituents) may, for example, have one or more substituents from the following series of halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy , amino, alkylamino, dialkylamino, cyano, nitro, ═O, —CHO, COOH, —COO — C ₁ —C ₆ alkyl, —SC ₁ —C ₆ alkyl.

 Alkenyl groups (and when they are components of other substituents) mean branched or unbranched alkenyl groups with carbon atoms from 2 to 10, preferably carbon atoms from 2 to 3, containing at least one double a bond, for example, and the above alkyl groups, if they contain at least one double bond, such as vinyl (provided that unstable enamines or enol ethers are not formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.

Substituted alkenyl groups, unless otherwise indicated (and if they are components of other substituents) may have one or more substituents from the following series of halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy, amino -, alkylamino, dialkylamino, cyano, nitro group, = O, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl and -SC ₁ -C ₆ -alkyl.

 Under alkynyl groups (and, when they are components of other substituents) understand alkynyl groups with the number of carbon atoms from 2 to 10, which contain at least one triple bond, for example, ethynyl, propargyl, butynyl, pentynyl, hexynil.

Substituted alkynyl groups, unless otherwise specified, (and when they are components of other substituents) may have one or more substituents from the series halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy, amino -, alkylamino, dialkylamino, cyano, nitro group, = O, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl.

 Cycloalkyl radicals with a carbon number of 3 to 6 are understood to mean cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may be substituted by a branched or unbranched alkyl group with a number of carbon atoms from 1 to 4, a hydroxy group and / or halogen, or as specified above. By halogen is meant fluorine, chlorine, bromine or iodine.

By aryl is meant an aromatic cyclic system containing from 6 to 10 carbon atoms, which, unless otherwise specified, may have substituents from the series C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, halogen, hydroxy, mercapto -, amino, alkylamino, dialkylamino group, CF ₃ -, cyano, nitro group, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl. A preferred aryl radical is phenyl.

 Examples of 5- or 6-membered heterocycles attached via a carbon atom that contain heteroatoms such as nitrogen, oxygen or sulfur include furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, tetrahydrofuranone, γ-butylrolactone, α-pyran , γ-pyran, dioxalane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine pyridine, piperidine, piperidine , triazine, tetrazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine, and the heterocycle may be substituted, as indicated in the refinements.

 "= O" means an oxygen atom attached via a double bond.

The present invention describes compounds that unexpectedly show high affinity for the following types of receptors: "Na ⁺ channel site 2" binding site, histamine H1 receptor, 5-hydroxytryptamine 1A receptor, 5-hydroxytryptamine 2A receptor, sigma receptor. In addition, these compounds exhibit antagonistic activity at the AMPA receptor.

 The neuroprotective effect of the compounds of the invention has been confirmed in animals. Based on these results, the compounds according to the invention can be used for neurodegenerative diseases, as well as for ischemia of the brain of various origins.

 Compounds according to the invention can be obtained using known methods, among others, and as described below.

 In the first step, the nitrile of general formula (I), relying on methods known from the literature (LFTietze, T. Eicher, "Reaktionen und Sinthesen im Organisch-chemischen Praktikum und Forschungslaboratorium", 2nd ed. 1991, Georg Thieme Verlag Stuttgart, New York , p. 340), when reacted with hydroxylamine, they are converted to the amidoxime of the general formula (2) (Scheme 1). The reaction of this amidoxime (2) under alkaline reaction conditions with derivatives of benzoic acid substituted by nucleophilic groups of the general formula (3) gives oxadiazoles of the general formula (4). Derivatives of benzoic acid (3), which have side chains with functional groups, can be used when appropriate protective groups are used.

 Alkali or alkaline earth metal alcoholates, for example, methanol, ethanol, isopropanol, n-, sec- and tert-butyl alcohol, are suitable as bases. Suitable alkali and alkaline earth metals are lithium, sodium, potassium, magnesium, calcium. Sodium methylate, sodium ethylate, sodium isopropylate, potassium tert-butylate and potassium methylate are particularly preferred as bases. Furthermore, bases such as hydrides of alkali and alkaline earth metals are suitable according to the invention.

в которой L' = отщепляемая групп, например хлор, бром или алкоксигруппа;
L = отщепляемая группа, например, хлор, бром, иод, метансульфонил;
Nu = -ОН, -SH, -NH₂ =VH, согласно вышеприведенным уточнениям, или
Nu = -B-OH, -B-SH, -B-NH₂ =B-VH согласно вышеприведенным уточнениям,
Sⁿ = S¹, S², S³, S⁴ или S⁵ согласно вышеприведенным уточнениям.

in which L '= a leaving group, for example chlorine, bromine or alkoxygroup;
L = a leaving group, for example, chloro, bromo, iodo, methanesulfonyl;
Nu = —OH, —SH, —NH ₂ = VH, according to the above refinements, or
Nu = -B-OH, -B-SH, -B-NH ₂ = B-VH according to the above refinements,
S ⁿ = S ¹ , S ² , S ³ , S ⁴ or S ⁵ according to the above refinements.

 Modification of the side chain during the formation of oxadiazole derivatives of the general formula (Ia ') occurs according to Scheme 1 during the final reaction of the compound (4) with electrophilic compounds of the general formula (5). To this end, after adding one base in an inert solvent to oxadiazoles (4), an electrophilic compound (5) is added at room temperature and after a period of time up to 1 hour, preferably after 15 to 30 minutes, it is heated under reflux for 4 to 12 hours, preferably from 6 to 8 hours. After cooling to room temperature, most of the solvent is distilled off in vacuo, and the product, after washing and drying, is purified by crystallization or chromatography. According to the invention, alkali and alkaline earth hydrides are used as bases. Hydrides of sodium, lithium, potassium, and also magnesium, calcium are preferred. Suitable inert solvents are dimethylformamide, methylene chloride, and cyclic ethers such as tetrahydrofuran or, preferably, dioxane. Along with this, alkoxides of alkali and alkaline earth metals, for example methanol, ethanol, isopropanol, n-, sec-, tert-butanol, are used as bases. Suitable alkali and alkaline earth metals such as lithium, sodium, potassium, magnesium and calcium. Sodium methylate, sodium ethylate, sodium isopropylate, potassium tert-butylate and potassium methylate are used. The alkali and alkaline earth metal hydroxides of lithium, sodium, potassium, as well as magnesium and calcium are also used according to the invention, but sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in an alcohol or aqueous solution are preferred.

Oxadiazoles of the general formula (Ia), which instead of the phenyl ring contained in the formula (Ia ¹ ) contain a heteroaromatic ring, are prepared in a similar manner.

The reaction of aromatic nitrides of the general formula (6) with electrophiles of the general formula (5) gives, according to Scheme 2, aromatic cyanides substituted by the side chain S ⁿ (n = 1, 2, 3, 4), of the general formula (7). In this case, the nitriles (6) after adding the base in an inert solvent at room temperature or when heated, preferably from 40 to 80 ^{o, are} deprotonated and finally electrophiles are added (5). The resulting solution was heated from 40 to 80 ^° for a period of time from 0.25 to 2 hours, and after cooling to room temperature, the solvent was distilled off in vacuo. This product, after washing and drying without further purification, is directly introduced into the next stages. According to the invention, alkali and alkaline earth hydrides are used as a base, preferably sodium, lithium, potassium, and also magnesium and calcium hydrides. Suitable inert solvents are dimethylformamide, methylene chloride, as well as cyclic ethers such as tetrahydrofuran, preferably dioxane.

в которой L' = отщепляемая группа, например хлор, бром, алкоксигруппа;
L = отщепляемая группа, например хлор, бром, иод, метансульфонил;
Nu = ОН, SH, NH₂ =VH согласно вышеприведенным уточнениям, или
Nu = -B-OH, -B-SH, -B-NH₂ =B-VH согласно вышеприведенным уточнениям;
Sⁿ=S¹, S², S³, S⁴ или S⁵ согласно вышеприведенным уточнениям.

in which L '= a leaving group, for example chlorine, bromine, alkoxygroup;
L = a leaving group, for example chloro, bromo, iodo, methanesulfonyl;
Nu = OH, SH, NH ₂ = VH according to the above refinements, or
Nu = -B-OH, -B-SH, -B-NH ₂ = B-VH according to the above refinements;
S ⁿ = S ¹ , S ² , S ³ , S ⁴ or S ⁵ according to the above refinements.

 These nitriles are converted in a known manner (LF Tietze, T. Eicher, "Reactions and Syntheses in an Organic-Chemical Workshop and in a Research Laboratory", Georg Thieme Verlag, Stuttgart, 2nd ed., 1991, p. 340) into aromatic amidoximes of the general formula ( 8). In an alkaline environment, these amidoximes, when reacted with carboxylic acid derivatives (9), form oxadiazoles of the formula (Ib '). To do this, amidoximes (8) with carboxylic acid derivatives (9) are dissolved in an inert solvent, preferably in alcohol, particularly preferably in ethanol, and when exposed to a base, they are heated. After cooling to room temperature, most of the solvent is distilled off in vacuo and the product after washing and drying is purified by crystallization or chromatography. Alkali or alkaline earth metal alcoholates of methanol, ethanol, isopropanol, n-, sec- and tert-butyl alcohol are suitable as bases. Suitable alkali and alkaline earth metals are: lithium, sodium, potassium, magnesium, calcium. As bases, sodium methylate, sodium ethylate, sodium isopropylate, potassium tert-butylate and potassium ethylate are particularly preferred.

 Oxadiazoles of the general formula (Ib), which instead of the phenyl ring contained in the formula (Ib ') contain a heteroaromatic ring, are prepared in a similar manner. Oxadiazoles of the general formula (Ib) having functional groups in the side chain are prepared using suitable protecting groups.

 Oxadiazole derivatives of the general formula (10), which have a side chain in the aromatic ring substituted by a leaving group, are converted according to the invention by reaction with nucleophiles of the general formula (11) into compounds of the general formula (I ') (see Scheme 3).

в которой L = отщепляемая группа, например хлор, бром, иод, метансульфонил,
S' = -B-V-D, -V-D, причем В, V и D приведены выше в уточнениях,
Sⁿ = S¹, S², S³, S⁴ или S⁵ имеют вышеуточненные значения.Scheme 3:

in which L = a leaving group, for example chlorine, bromine, iodine, methanesulfonyl,
S '= -BVD, -VD, with B, V and D given above in the refinements,
S ⁿ = S ¹ , S ² , S ³ , S ⁴ or S ⁵ have the above values.

For this, compound (10) is dissolved in an inert solvent and, after the addition of the nucleophile (11), is heated for 0.5 to 2 hours, preferably 1 to 1.5 hours, at a temperature of 50 to 120 ^° C. After cooling to room temperature at temperature, most of the solvent is distilled off in vacuo, and the product, after washing and drying, is purified by crystallization or chromatography.

 Suitable inert solvents are dimethylformamide, methylene chloride, as well as cyclic ethers such as tetrahydrofuran or preferably dioxane.

 Oxadiazoles of the general formula (I), which instead of the phenyl ring contained in the formula (I ′) contain a heteroaromatic ring, are obtained in a similar way and manner. The synthesis of oxadiazoles of the general formula I having functional groups in the side chains is carried out using suitable protecting groups.

 The following are a few detailed descriptions of the synthesis illustrating the invention, but the subject matter is not limited to them.

а) Получение амидоксима бензойной кислоты:
14 г гидрохлорида гидроксиламина растворяют в 50 мл воды и при перемешивании и охлаждении льдом добавляют 16,8 г гидрогенкарбоната натрия. К этой смеси добавляют раствор 10,3 г нитрила бензойной кислоты в 100 мл этанола и 3 часа нагревают при обратной перегонке. В заключение этанол отгоняют в вакууме и остаток 2 раза экстрагируют диэтиловым эфиром. Объединенные эфирные фазы сушат над сульфатом натрия и отгоняют растворитель. Остаток (13,4 г = 98,5% от теор.) без дальнейшей очистки вводят в реакцию циклизации.Example 1: 5- {2- [2- (N, N-dimethylamino) ethyl] oxymethyl-phenyl} -3-phenyl-1,2,4-oxadiazole

a) Obtaining amidoxime benzoic acid:
14 g of hydroxylamine hydrochloride are dissolved in 50 ml of water and 16.8 g of sodium hydrogen carbonate are added with stirring and cooling with ice. To this mixture was added a solution of 10.3 g of benzoic acid nitrile in 100 ml of ethanol and heated for 3 hours under reflux. Finally, ethanol is distilled off in vacuo and the residue is extracted 2 times with diethyl ether. The combined ether phases are dried over sodium sulfate and the solvent is distilled off. The residue (13.4 g = 98.5% of theory.) Without further purification is introduced into the cyclization reaction.

b) Preparation of 5- (2-hydroxymethyl-phenyl) -3-phenyl-1,2,4-oxadiazole:
1.36 g of benzoic acid amidoxime is added to a freshly prepared solution of 0.46 g of sodium in 50 ml of anhydrous ethanol and stirred for 15 minutes. Finally, 2.68 g of phthalide is added with stirring and heated for 15 hours under reflux. The dark red solution was dried in vacuo and the residue was dissolved in water. It is neutralized with 2N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulfate, the solvent is distilled off and chromatographed on silica gel with dichloromethane / methanol (98: 2).

 Yield 1.2 g (48% of theory).

а) Получение 5-(2-гидроксифенил)-3-фенил-1,2,4-оксадиазола:
6,8 г амидоксима бензойнов кислоты и 15,2 г метилового эфира салициловой кислоты растворяют в 150 мл безводного этанола, добавляют 2,3 г натрия и 3 раза нагревают по 25 минут (с 5-минутными перерывами) в микроволновой печи мощностью 400 ватт. Реакционную смесь уменьшают до ^l/₃ объема в вакууме и к остатку добавляют воду. При охлаждении добавлением 2Н соляной кислоты устанавливают рН 8-9, образующийся осадок отсасывают и промывают водой. Для полного удаления воды его растворяют в дихлорметане и сушат над сульфатом натрия и отгоняют растворитель. Выход: 12,9 г (92% от теор. в пересчете на амидоксим бензойной кислоты). Температура плавления: 156-158^oС.c) Preparation of 5- {2- [2- (N, N-dimethylamino) ethyl] oxymethyl-phenyl} -3-phenyl-1,2,4-oxadiazole:
1 g of 5- (2-hydroxymethyl-phenyl) -3-phenyl-1,2,4-oxadiazole is dissolved in 20 ml of dimethylformamide (DMF) and 0.2 g of sodium hydride (60% in oil) is added. Then stirred for 30 minutes at 20-23 ^o C and add pre-mixed for 30 minutes a mixture of 2-N, N-dimethylaminoethyl chloride and 0.22 g of sodium hydride (60% in oil) in 20 ml of DMF. This mixture was heated at 100 ^{° C.} for 5 hours, then the solvent was distilled off in vacuo. The residue was dissolved in water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The aqueous phase is made basic with sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, the solvent is distilled off in vacuo and chromatographed on silica gel (methanol). The product is taken up in hydrochloride in an ether solution of HC1 and recrystallized from ethanol / ether. Yield 0.07 g (5% of theory.). Melting point: 107 ^o C (decomp.)
Example 2: 5- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole

a) Preparation of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole:
6.8 g of benzoic acid amidoxime and 15.2 g of salicylic acid methyl ester are dissolved in 150 ml of anhydrous ethanol, 2.3 g of sodium are added and 3 times heated for 25 minutes (with 5-minute breaks) in a 400-watt microwave. The reaction mixture was reduced to ^l / ₃ volume in vacuo and water was added to the residue. Under cooling, by adding 2N hydrochloric acid, a pH of 8-9 is established, the precipitate formed is filtered off with suction and washed with water. To completely remove water, it is dissolved in dichloromethane and dried over sodium sulfate and the solvent is distilled off. Yield: 12.9 g (92% of theory. In terms of benzoic acid amidoxime). Melting point: 156-158 ^o C.

b) Preparation of 5- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole:
2.38 g of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole is dissolved in 100 ml of anhydrous dioxane and 0.3 g of an 80% suspension of sodium hydride in oil is added and 15 minutes at a temperature of 25-30 ^o With mix. To this solution was added 60 ml of anhydrous dioxane, to which 2.88 g of 2- (N, N-dimethylamino) ethyl chloride hydrochloride and 0.6 g of an 80% suspension of sodium hydride in oil were added. This solution is also stirred for 15 minutes at a temperature of 25-30 ^o C. the Combined solutions are heated for 8 hours under reverse distillation, left overnight and evaporated in vacuum. Water and 20 ml of 1 N sodium hydroxide are added to the residue and spent
extraction with ethyl acetate. The organic phase was dried over sodium sulfate, the solvent was evaporated in vacuo, and the residue was chromatographed on silica gel with ethyl acetate / isopropanol (70:30, to which 2.5% 25% ammonia solution was added). The base thus obtained is dissolved in anhydrous ethanol, acidified with a solution of HCl in ether and precipitated with diethyl ether. The precipitate was recrystallized from anhydrous ethanol and diethyl ether. Yield: 2.2 g (64% of theory), melting point: 186-187 ^o C.

а) Получение 2-[2-(N, N-диметиламино)этилокси]-(нитрила бензойной кислоты):
23,8 г 2-гидрокси (нитрила бензойной кислоты) перемешивают с 6,0 г 80%-ной суспензии гидрида натрия в масле и с 200 мл диоксана в течение 30 минут при 60^oС. К этому раствору добавляют 100 мл безводного диоксана, к которому добавлено 28,8 г гидрохлорида 2-(N,N-диметиламино)этилхлорида и 6,0 г 80%-ной суспензии гидрида натрия в масле. Этот раствор также перемешивают 30 минут при 60^oС. Объединенные растворы нагревают 4 раза по 8 минут в микроволновой печи при мощности 400 ватт и затем растворитель выпаривают в вакууме. К остатку добавляют воду и 1Н едкий натр и экстрагируют диэтиловым эфиром. Органическую фазу высушивают над сульфатом натрия, а растворитель выпаривают в вакууме. Выход: 19,6 г (52% от теор.).Example 3: 3- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -5-phenyl-1,2,4-oxadiazole:

a) Preparation of 2- [2- (N, N-dimethylamino) ethyloxy] - (benzoic acid nitrile):
23.8 g of 2-hydroxy (benzoic acid nitrile) was mixed with 6.0 g of an 80% suspension of sodium hydride in oil and with 200 ml of dioxane for 30 minutes at 60 ^° C. To this solution was added 100 ml of anhydrous dioxane, to which 28.8 g of 2- (N, N-dimethylamino) ethyl chloride hydrochloride and 6.0 g of an 80% suspension of sodium hydride in oil are added. This solution was also stirred for 30 minutes at 60 ^° C. The combined solutions were heated 4 times for 8 minutes in a microwave oven at 400 watts and then the solvent was evaporated in vacuo. Water and 1N sodium hydroxide were added to the residue and extracted with diethyl ether. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. Yield: 19.6 g (52% of theory).

b) Preparation of 2- [2- (N, N-dimethylamino) ethyloxy] (benzoic acid amidoxime):
14 g of hydroxylamine hydrochloride are dissolved in 100 ml of water and 16.8 g of sodium hydrogen carbonate are added portionwise with stirring. To this mixture was added a solution of 19.0 g of 2- (N, N-dimethylamino) ethyloxy- (nitrile of benzoic acid) in 150 ml of ethanol and heated under reflux for 5 hours. After that, ethanol was evaporated in vacuo and the residue was extracted 2 times with diethyl ether. The combined ether phases are dried over sodium sulfate and the solvent is evaporated. The residue (16 g equal to 72% of theory.) Is used in the cyclization reaction without further purification.

c) Preparation of 3- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -5-phenyl-1,2,4-oxadiazole:
4.46 g of 2- (N, N-dimethylamino) ethyloxy- (amidoxime benzoic acid) and 5.44 g of benzoic acid methyl ester are dissolved in 150 ml of absolute ethanol, 2.3 g of sodium are added and heated 2 times for 11 minutes ( with a break of 5 minutes) in a microwave oven with a power of 300 watts. The reaction mixture was evaporated in vacuo, water was added to the residue and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is evaporated off under vacuum, and the residue is chromatographed on silica gel with ethyl acetate / isopropanol (70: 30, with the addition of 2.5% 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with a solution of HCl in ether and precipitated with diethyl ether. The residue was recrystallized from anhydrous ethanol and diethyl ether. Yield: 2.5 g (36% of theory). Melting point: 174-175 ^o C.

2,38 г 5-(2-гидроксифенил)-3-фенил-1,2,4-оксадиазола растворяют в 100 мл безводного диоксана и перемешивают с 0,3 г 80%-ной суспензии гидрида натрия в масле в течение 15 минут при 25-30^oС. К этому раствору добавляют 75 мл абсолютного диоксана, к которому добавлено 3,72 г гидрохлорида 2-(морфолино)этиленхлорида и 0,6 г 80%-ной суспензии гидрида натрия в масле. Этот раствор также перемешивают 15 минут при 25-30^oС. Эти объединенные растворы нагревают 6 часов при 100^oС и в заключение растворитель испаряют в вакууме. К остатку добавляют воду и 20 мл 1N едкого натра и экстрагируют уксусным эфиром. Органическую фазу сушат над сульфатом натрия, растворитель отгоняют под вакуумом и остаток хроматографируют на силикагеле с уксусным эфиром/изопропанолом (70:30, к которым добавлено 1,5% 25%-ного раствора аммиака). Основание, полученное таким образом, растворяют в безводном этаноле, подкисляют эфирным раствором НС1 и высаживают диэтиловым эфиром. Остаток перекристаллизовывают из безводного этанола и диэтилового эфира. Выход: 1,9 г (49% от теор.). Температура плавления 194-195^oС.Example 4: 5- {2- [2- (morpholino) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole

2.38 g of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and mixed with 0.3 g of an 80% suspension of sodium hydride in oil for 15 minutes at 25-30 ^o C. To this solution add 75 ml of absolute dioxane, to which 3.72 g of 2- (morpholino) ethylene chloride hydrochloride and 0.6 g of an 80% suspension of sodium hydride in oil are added. This solution was also stirred for 15 minutes at 25-30 ^° C. These combined solutions were heated for 6 hours at 100 ^{° C.} and finally the solvent was evaporated in vacuo. Water and 20 ml of 1N sodium hydroxide are added to the residue and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel with ethyl acetate / isopropanol (70:30, to which 1.5% 25% ammonia solution is added). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue was recrystallized from anhydrous ethanol and diethyl ether. Yield: 1.9 g (49% of theory). Melting point 194-195 ^o C.

а) Получение 5-[2-(2-бромэтил)окси-фенил]-3-фенил-1,2,4-оксадиазола:
1,85 г 5-(2-гидроксифенил)-3-фенил-1,2,4-оксадиазола растворяют в 80 мл метилэтилкетона и добавляют 5 мл 1,2-дибромметана, 6 г карбоната калия и 0,1 г йодида калия. Смесь нагревают 12 часов при обратной перегонке и после охлаждения отфильтровывают осадок. Органическую фазу отделяют от растворителя в вакууме и хроматографируют на силикагеле вначале с толуолом, а затем дихлорметаном в качестве элюента. Выход: 2,3 г (86% от теор.).Example 5: 5- {2- [2- (4-methylpiperazin-1-yl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole

a) Preparation of 5- [2- (2-bromoethyl) hydroxyphenyl] -3-phenyl-1,2,4-oxadiazole:
1.85 g of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole are dissolved in 80 ml of methyl ethyl ketone and 5 ml of 1,2-dibromomethane, 6 g of potassium carbonate and 0.1 g of potassium iodide are added. The mixture is heated for 12 hours under reflux and after cooling, the precipitate is filtered off. The organic phase is separated from the solvent in vacuo and chromatographed on silica gel first with toluene and then with dichloromethane as eluent. Yield: 2.3 g (86% of theory).

b) Preparation of 5- {2- [2- (4-methylpiperazin-1-yl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole:
1.72 g of 5- [2- (2-bromoethyl) hydroxyphenyl] -3-phenyl-1,2,4-oxadiazole is dissolved in 50 ml of anhydrous dioxane and 2 g of N-methylpiperazine are added. The solution was heated for 1 hour under reflux and then the solvent was distilled off in vacuo. The residue was chromatographed on silica gel with dichloromethane / methanol (90:10). The base thus obtained is dissolved in anhydrous ethanol, acidified with a solution of HC1 in ether and precipitated with diethyl ether. The residue was recrystallized from anhydrous ethanol and diethyl ether. Exit; 1.7 g (78% of theory). Melting point: 251-253 ^o C.

 Example 6: 5-phenyl-3- [2- (4-methylpiperazin-1-yl) phenyl] -1,2,4-oxadiazole.

а) Получение 1-(2-цианофенил)пиперазина:
(по аналогии с G. Е.Martin, R.J.Elgin, J.R.Mathiasen, С.В.Davis, J.M. Kesslick, J. Med. Chem. 32 (1989), 1052-1056)
б) Получение 1-(2-цианофенил)-4-метилпиперазина:
7,48 г 1-(2-цианофенил)пиперазина растворяют в 30 мл формальдегида и 30 мл муравьиной кислоты, нагревают 1 час при обратной перегонке. Растворитель выпаривают в вакууме и остаток растворяют в эфире и добавляют воду. Подщелачивают 20%-ным раствором едкого натра, насыщают карбонатом калия и экстрагируют эфиром. Органическую фазу высушивают над сульфатом натрия и в вакууме отгоняют растворитель. Для очистки хроматографируют на силикагеле с уксусным эфиром/изопропанолом (70:30, при добавлении 1% 25%-ного раствора аммиака). Выход: 6,7 г (83% от теор.).

a) Obtaining 1- (2-cyanophenyl) piperazine:
(similar to G. E. Martin, RJElgin, JRMathiasen, C. B. Davis, JM Kesslick, J. Med. Chem. 32 (1989), 1052-1056)
b) Preparation of 1- (2-cyanophenyl) -4-methylpiperazine:
7.48 g of 1- (2-cyanophenyl) piperazine is dissolved in 30 ml of formaldehyde and 30 ml of formic acid, heated for 1 hour under reverse distillation. The solvent was evaporated in vacuo and the residue was dissolved in ether and water was added. It is alkalinized with a 20% sodium hydroxide solution, saturated with potassium carbonate and extracted with ether. The organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. For purification, it is chromatographed on silica gel with ethyl acetate / isopropanol (70:30, with the addition of 1% 25% ammonia solution). Yield: 6.7 g (83% of theory.).

 c) Obtaining amidoximes is carried out according to the method described in example 3b.

 g) Obtaining 1,2,4-oxadiazoles is carried out according to the method described in example 3B.

а) Получение 2-(пиперазин-1-ил)-(метилового эфира бензойной кислоты):
(по аналогии с G.S.Poindexter, M.A.Bruce, К.L.LeBoulluec, I.Monkovic, Tetrahedron Lett. 35 (1994), 7331-7334)
б) Получение 5-[2-(пиперазин-1-ил)-фенил]-3-фенил-1,2,4-оксадиазола:
К 1,36 г амидоксима бензойной кислоты и 2,34 г малеината 2-(пиперазин-1-ил)-(этилового эфира бензойной кислоты) добавляют 0,92 г натрия в 100 мл безводного этанола и 6 раз по 30 минут (с перерывами по 5 минут) нагревают в микроволновой печи с мощностью 350 ватт. После охлаждения растворитель отгоняют в вакууме. Остаток экстрагируют дихлорметаном из воды. Органическую фазу сушат над сульфатом натрия и отгоняют растворитель в вакууме. Остаток хроматографируют на силикагеле с уксусным эфиром/изопропанолом (70:30 при добавлении 5% 25%-ного раствора аммиака). Выход: 90 мг (3% от теор.). Температура плавления: 254-255^oС.Example 7: 3-phenyl-5- [2- (piperazin-1-yl) phenyl] -1,2,4-oxadiazole

a) Preparation of 2- (piperazin-1-yl) - (benzoic acid methyl ester):
(similar to GSPoindexter, MABruce, K.L. LeBoulluec, I. Monkovic, Tetrahedron Lett. 35 (1994), 7331-7334)
b) Preparation of 5- [2- (piperazin-1-yl) phenyl] -3-phenyl-1,2,4-oxadiazole:
To 1.36 g of benzoic acid amidoxime and 2.34 g of 2- (piperazin-1-yl) - (benzoic acid ethyl ester) maleate, 0.92 g of sodium in 100 ml of anhydrous ethanol are added and 6 times in 30 minutes (intermittently) for 5 minutes) are heated in a microwave with a power of 350 watts. After cooling, the solvent was distilled off in vacuo. The residue was extracted with dichloromethane from water. The organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue was chromatographed on silica gel with ethyl acetate / isopropanol (70:30 with the addition of 5% 25% ammonia solution). Yield: 90 mg (3% of theory). Melting point: 254-255 ^o C.

а) Получение 2-[2-(N, N-диметхламино)этил] окси-(метилового эфира бензойной кислоты):
15,2 г метилового эфира салициловой кислоты растворяют в 200 мл безводного ацетонитрила, добавляют 4,4 г 60%-ной суспензии гидрида натрия в масле и перемешивают 60 минут при комнатной температуре. К этому раствору добавляют 200 мл абсолютного ацетонитрила, в который добавлено 17,4 г гидрохлорида 2-(N,N-диметиламино)этилхлорида и 5,2 г 60%-ной суспензии гидрида натрия в масле. Этот раствор также перемешивают 60 минут при комнатной температуре. Объединенные растворы нагревают 1 час при обратной перегонке и затем отгоняют растворитель в вакууме. К остатку добавляют воду и экстрагируют уксусным эфиром. Органическую фазу сушат над сульфатом натрия, растворитель отгоняют в вакууме, а остаток хроматографируют на силикагеле с уксусным эфиром/метанолом (1:1). Получают 14,6 г желтого масла (65% от теор. ).Example 8: 5- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -3- (4-hydroxyphenyl) -1,2,4-oxadiazole

a) Preparation of 2- [2- (N, N-dimethlamino) ethyl] hydroxy- (benzoic acid methyl ester):
15.2 g of salicylic acid methyl ester are dissolved in 200 ml of anhydrous acetonitrile, 4.4 g of a 60% suspension of sodium hydride in oil are added and stirred for 60 minutes at room temperature. To this solution was added 200 ml of absolute acetonitrile, to which 17.4 g of 2- (N, N-dimethylamino) ethyl chloride hydrochloride and 5.2 g of a 60% suspension of sodium hydride in oil were added. This solution was also stirred for 60 minutes at room temperature. The combined solutions are heated for 1 hour under reflux and then the solvent is distilled off in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel with ethyl acetate / methanol (1: 1). Obtain 14.6 g of a yellow oil (65% of theory.).

b) Preparation of 2- [2- (N, N-dimethylamino) ethyl] hydroxy- (benzoic acid):
4.4 g of 2- [2- (N, N-dimethylamino) ethyl] hydroxy- (benzoic acid methyl ester) is heated with 30 ml of 5N hydrochloric acid for 15 minutes in a 300-watt microwave. After that, it is extracted with ethyl acetate, the aqueous phase is evaporated and recrystallized from acetonitrile / ether. Yield: 4.2 g (86% of theory.)
c) Preparation of 5- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -3- (4-hydroxyphenyl) -1,2,4-oxadiazole;
2.45 g of 2- [2- (N, N-dimethylamino) ethyl] hydroxy- (benzoic acid), 1.91 g of N-ethyl- (N-dimethylaminopropyl) carbodiimide hydrochloride and a catalytic amount of hydroxybenzotriazole are dissolved in 50 ml of DMF. After 15 minutes, 1.52 g of 4-hydroxy (benzoic acid amidoxime) was added and heated for 15 minutes in a microwave at a power of 700 watts. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and the solvent was distilled off in vacuo. The residue was filtered on silica gel with ethanol and converted to salt as described above. Yield: 1.1 g (29% of theory). Melting point 170 ^o C (decomp.).

3,57 г 5-(2-гидроксифенил)-3-фенил-1,2,4-оксадиазола растворяют в 70 мл безводного ДМФ и перемешивают с 0,6 г 60%-ной суспензии гидрида натрия в масле в течение 30 минут при температуре 25-30^oС. К этому раствору добавляют 1,4 г амида 2-хлоруксусной кислоты и перемешивают 2 часа при 100^oС. После этого отгоняют растворитель в вакууме. К остатку добавляют воду и отсасывают. Осадок вываривают последовательно в метаноле и в этиловом эфире уксусной кислоты. Выход: 3/3 г (75% от теор.). Температура плавления: 249-251^oС.Example 9: 5- {2 - [(carboxamido) methyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole

3.57 g of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole are dissolved in 70 ml of anhydrous DMF and mixed with 0.6 g of a 60% suspension of sodium hydride in oil for 30 minutes at a temperature of 25-30 ^o C. 1.4 g of 2-chloroacetic acid amide was added to this solution and stirred for 2 hours at 100 ^o C. After that, the solvent was distilled off in vacuo. Water is added to the residue and suction filtered. The precipitate was boiled successively in methanol and ethyl acetate. Yield: 3/3 g (75% of theory). Melting point: 249-251 ^o C.

а) Получение 5-{2-[2-[1,3-диоксан-2-ил)этил]окси-фенил}-3-фенил-1,2,4-оксадиазола:
4,1 г 5-(2-гидроксифенил)-3-фенил-1,2,4-оксадиазола растворяют в 60 мл безводного ДМФ и добавляют 0,688 г 60%-ной суспензии гидрида натрия в масле. К этой смеси добавляют 3,15 г 2-(2-бромэтил)-1,3-диоксана и перемешивают 4 часа при 100^oС. После охлаждения растворитель отгоняют в вакууме и к остатку добавляют воду. Его экстрагируют уксусным эфиром, органическую фазу высушивают над сульфатом натрия и в вакууме отгоняют растворитель. Остающийся раствор хроматографируют на силикагеле с этиловым эфиром уксусной кислоты. Выход: 2,5 г (41% от теор.).Example 10: 5- {2- [2- (carboxamido) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole

a) Preparation of 5- {2- [2- [1,3-dioxan-2-yl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole:
4.1 g of 5- (2-hydroxyphenyl) -3-phenyl-1,2,4-oxadiazole are dissolved in 60 ml of anhydrous DMF and 0.688 g of a 60% suspension of sodium hydride in oil is added. 3.15 g of 2- (2-bromoethyl) -1,3-dioxane was added to this mixture and stirred for 4 hours at 100 ^° C. After cooling, the solvent was distilled off in vacuo and water was added to the residue. It is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The remaining solution is chromatographed on silica gel with ethyl acetate. Yield: 2.5 g (41% of theory).

b) Preparation of 5- {2- [2- (carboxyl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole:
2.5 g of 5- {2- [2- (1,3-dioxan-2-yl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole are dissolved in 50 ml of acetone and at 0 ^o A solution of chromium oxide (VI) in 30% sulfuric acid is added dropwise. Then, it is stirred for 20 hours at 20-23 ^{° C.} and 25 ml of isopropanol are added under cooling at 5 ^{° C.} The mixture is added to a suspension of 100 ml of dichloromethane and 100 ml of water and the organic phase is separated. The aqueous phase is again extracted with dichloromethane and the combined organic solutions are again with water. It is dried over sodium sulfate, the solvent is distilled off in vacuo and chromatographed on silica gel with dichloromethane / ethyl acetate (97: 3). The product was recrystallized from ethyl acetate. Yield: 0.23 g (11% of theory). Melting point: 170-171 ^o C.

c) Preparation of 5- {2- [2- (carboxamido) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole:
0.8 g of 5- {2- [2- (carboxyl) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole is dissolved in 40 ml of anhydrous dichloromethane and cooled to 0 ^° C. To this solution is added 2 ml of oxalyl chloride dissolved in 5 ml of anhydrous dichloromethane and stirred for 1.5 hours at 20 ^° C. The solvent was distilled off in vacuo and 30 ml of anhydrous dichloromethane was added. While cooling, an ammonia dichloromethane solution is added until the reaction volume is alkaline. Leave for 14 hours, add water, the precipitate formed and the dichloromethane phase are separated and the organic phase is dried over sodium sulfate. After distillation of the solvent, a residue of 0.7 g was obtained. This residue was chromatographed on silica gel with dichloromethane / methanol (98: 2) and the product was recrystallized from ethyl acetate. Yield: 0.24 g (33% of theory). Melting point: 137-138 ^o C.

 By analogy with the above methods and examples of syntheses were obtained including the following compounds (see table 1 and 2).

 It was unexpectedly discovered that the compounds corresponding to the invention exhibit affinity for different receptors or activity on different types of receptors and exhibit a neuroprotective effect.

 In vivo and in vitro experiments have shown that cell damage and cessation of their functioning in the brain as a result of hypoglycemia, hypoxia, anoxia, global or focal ischemia, traumatic brain injury, cerebral edema, and increased intracranial pressure are partially associated with increased synaptic activity and enhanced in connection with this release of transmitters. Along with glutamate, histamine and serotonin are particularly important neurotransmitters. In addition, there is a change in the concentration of ions, especially calcium and sodium ions.

 It is known that after the systematic administration of glutamate, neurons in the brain of mice are destroyed (S.M. Rothman, T.W. Olney, Trends in Neurosciences, 10 (1987) 299). This result allows us to conclude that glutamate plays a role in neurodegenerative diseases (R. Schwarcz, B. Meldrum, The Zancet 11 (1985) 140). In addition, it is known that such substances as quisqualic acid, kainic acid, ibotenic acid, glutamic acid, N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) are exogenous, respectively, endogenous neurotoxins. Brain lesions that can be induced by such substances are comparable to lesions that occur in connection with epilepsy and other neurodegenerative diseases such as Huntington's disease or Alzheimer's disease. Substances and ions that inhibit the activity of glutamate receptors and the ion channel associated with this receptor, such as competing and non-competing antagonists of excitatory amino acids, protect brain cells from hypoxic and ischemic damage. These results indicate that glutamate receptors play an important role in the transmission of ischemic damage.

 Evidence of the effect on the AMPA receptor was obtained using electrophysiology on neural cells (patch-clamp method) (M. L. Mayer, L. Vyklicky, G. L. Westbrook, J. Physiol. 415 (1989) 329-350). Testing was carried out at a concentration of test substance of 100 μM (see table 3).

Evidence of affinity for the site of attachment of the "Na ⁺ channel site" was obtained as described by GWBrown (J.Newrosci. 6 (1986) 2064).

 Testing was carried out in a typical way, at a concentration of the test substance of 10 μM (see table 4).

 Damage to cells with hypoglycemia, hypoxia, anoxia, and ischemia results from insufficient supply of reduced energy supply, such as glucose in neurons.

 The effect of histamine receptor antagonists on impaired absorption of 2-deoxyglucose induced by hypoxia and hypoglycemia was studied in rat "Hippocampus Slice" preparations (S.Shibata, S.Watanase, Neuroscience Letters 151 (1993) 138). The addition of histamine further exacerbates the decrease in ischemia-induced 2-deoxyglucose uptake. It has been shown that histamine H1 receptor antagonists improve the absorption of 2-deoxyglucose, a decrease in which is induced by ischemia, while histamine H2 receptor antagonists do not affect it. The protective effect of histamine H1 receptor antagonists can be eliminated with histamine. This study showed that histamine receptors play an important role in reducing glucose metabolism induced by ischemia.

 Excessive neuronal activity in combination with a massive increase in neurotransmitters can lead to neuronal degeneration in animal models with unsteady cerebral ischemia (A. Benveniste, H. Drejer, A. Schousboe, N. H. Diemer, J. Neurochem. 43 (1984) 1369). Neuronal activity can be inhibited by substances that bind neurotransmitters to receptors such as 5-hydroxytryptamine (serotonin) (R. Andrade, R. A. Nicoll, Soc. Neurosci. Abstr. 11 (1985) 297). In addition, it was shown that the administration of 5-hydroxytryptamine agonists in animal models with occlusion of the middle cerebral artery leads to a decrease in infarction (JHMPren, C. Backhauss, C. Karkoutly, J. Nuglisch, B. Peruche, C. Rossberg, J. Krieglstein, Eur. J. Pharmacol. 203 (1991) 213).

 As a test system to prove affinity for the following receptors, studies on receptor binding were carried out, based on the following works: histamine H1 (H1) receptor (S. Dini et al. Agents and Actions 33 (1991) 181); 5-hydroxytryptamine 1A (HT1A) receptor (M.D. Hall and coworkers, J. Neurochem. 44 (1985) 1685); 5-hydroxytryptamine 2A (HT2A) receptor (J.H. Leysen et al., Mol. Pharmacol. 21 (1982) 301). Testing was carried out in a typical manner at a test substance concentration of 10 μM.

 Table 5 shows the inhibition values at the above receptors.

 According to H. Takahashi et al. (Stroke 26 (1995) 1676) sigma receptors are involved in the mechanism of acute damage after transient focal ischemia. Takahashi et al. it was possible, for example, to prove a decrease in infarction space in the study of a potential sigma receptor ligand in a model of transient focal ischemia.

 As a test system for proving the affinity of the compounds of the invention for the sigma receptor, receptor binding studies have been performed according to (E.W. Karbon, K. Naper, M.J. Pontecorvo Eur. J. Pharmacol. 193 (1991) 21). Testing was carried out in a typical manner at a test substance concentration of 10 μM. The braking values are shown in table 6.

 Evidence of a neuroprotective effect in vivo was obtained on a rat model of apoplexy shock. For this, permanent focal cerebral ischemia is induced as a result of surgical occlusion of Arteria cerebri media (MCAO) (based on the work of A. Tamura, DIGraham, J. McCulloch and GMTeasdale, J. Cereb. Blood Metab. 1 (1981) 53-60) . Using 5- {2- [2- (N, N-dimethylamino) ethyl] hydroxyphenyl} -3-phenyl-1,2,4-oxadiazole (Example 2), the lesion area was clearly and significantly reduced.

 The above results prove that oxadiazole derivatives of the general formula I can be used for neurodegenerative diseases and cerebral ischemia of various origins. These include, for example, epilepsy, hypoklemia, hypoxia, anoxia, brain trauma, cerebral edema, amyotropic lateral sclerosis, Huntington’s disease, Alzheimer's disease, hypotension, cardiac infarction, increased intracranial pressure, ischemic paralysis and hemorrhage, global cerebral ischemia with cardiac arrest, diabetic polyneuropathy, tinitus, perinatal asphyxia, psychosis, schizophrenia, depression and Parkinson's disease.

 The compounds of general formula (I) are used individually or in combination with other compounds of the invention, optionally and in combination with other pharmacologically active substances. Suitable forms for use are, for example, tablets, capsules, suppositories and solutions, especially injection solutions (s.c., i.v., i.m.) and infusion syrups, emulsions or dispersible powders. Moreover, the proportion of the pharmaceutically active substance is from 0.1 to 90 wt.%, Preferably from 0.5 to 50 wt.% Of the total composition, that is, in quantities that are sufficient to achieve the dosage ranges given below. Suitable tablets are prepared, for example, by mixing one or more active ingredients with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, by spraying agents such as corn starch or alginic acid, binders such as starch and gelatin, lubricants such as magnesium stearate or talc and / or means to achieve a prolongation effect such as carboxymethyl cellulose, acetone cellulose phthalate, or polyvinyl acetate. Tablets may also consist of many layers.

 Accordingly, dragees can be obtained by coating nuclei obtained analogously to tablets with substances which are usually used to coat dragees such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve the effect of prolongation or to avoid incompatibility, the core may also consist of several layers. Similarly, for the prolongation effect, a dragee coating, consisting of several layers, can also be used, using the same excipients as mentioned above and used for tablets.

 Syrups of the active compounds, optionally a combination of the active ingredients of the invention, may contain sweeteners such as saccharin, cyclamate, glycerin or sugar, as well as taste improvers, such as flavorings such as vanillin or orange extract. In addition, they may contain adjuvants for the formation of suspensions, thickening agents, such as sodium carboxymethyl cellulose, crosslinking agents, for example, condensation products of fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoate.

 Injection and infusion solutions are obtained in the usual way, for example, by adding isotonants, preserving agents such as p-hydroxybenzoates, or stabilizers such as alkali metal salts with ethylene diamine tetraacetic acid, if necessary using emulsifying agents and / or dispersing agents, and when using water in as a diluent, if necessary, organic solvents can be used as intermediaries in the dissolution or auxiliary solvents, and fill in injection bottles or ampoules, or infusion bottles.

 A capsule can be made containing one or more active ingredients, if necessary, a combination of active ingredients, the active ingredients being mixed with inert carriers such as milk sugar or sorbitol and filled into gelatin capsules.

 Suitable candles can, for example, be made by mixing with carriers provided for this, such as neutral fats or polyethylene glycols, if necessary, their derivatives. As auxiliary substances, for example, water, formally safe organic solvents such as paraffins (e.g. oil fractions), vegetable oils (e.g. peanut oil, sesame oil), mono- or polyfunctional alcohols (e.g. ethanol, glycerin) can be mentioned. ), carrier materials such as rock grinding (e.g. kaolin, alumina, talc, chalk), grinding of synthetic inorganic materials (highly dispersed silicic acid and silicates), sugar (cane, milk or grape sugar), emulsifying agents (e.g. lignin, spent sulfite liquor, methyl cellulose, starch and polyvinyl pyrrolidone) and additives to improve processing (e.g. magnesium stearate, talc, stearic acid and sodium laurate sulfate).

 The use is carried out in the usual way, preferably parenteral, especially by intravenous infusion.

 In the case of oral administration, tablets can, of course, contain, in addition to the carrier substances mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with other excipients such as starch, preferably potato starch, gelatin and the like. . In addition, agents for improving tablet processing, such as magnesium stearate, sodium laurosulfate, and talc, can be shared. In the case of aqueous suspensions, flavoring agents or coloring agents can be added to the active substances, in addition to the above-mentioned auxiliary substances.

 In the case of parenteral administration, solutions of the active substances with suitable liquid carrier materials are used.

 The dosage for intravenous administration is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour. However, if necessary, a deviation from the indicated amounts is possible depending on the body weight, respectively, on the form of application, individual susceptibility to the drug, type of dosage form and time, respectively, from the interval between doses. So, in some cases it turns out to be sufficient to use less than the minimum amount, while in other cases it is necessary to exceed the upper limit. In the case of the use of large quantities, it is recommended that they be carried out with more receptions per day.

 In addition, compounds with the general formula (I), respectively, their salts with acids, can be combined with active substances of a different series.

The examples below illustrate the invention, but it is not limited to:
Examples of pharmaceutical forms
A) Pills - per tablet
Active ingredient - 100 mg
Milk Sugar - 140 mg
Corn Starch - 240 mg
Polyvinylpyrrolidone - 15 mg
Magnesium Stearate - 5 mg - 500 mg
The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, after which it is moistened with a solution of pyrrolidone in water, kneaded, granulated wet and dried. The granulate, the remainder of the corn starch and magnesium stearate are sieved and mixed together. Tablets of suitable weight and shape are pressed from the mixture.

B) Pills - per pill
Active ingredient - 80 mg
Milk Sugar - 55 mg
Corn Starch - 190 mg
Microcrystalline Cellulose - 35 mg
Polyvinylpyrrolidone - 15 mg
Sodium Carboxymethyl Starch - 23 mg
Marnia stearate - 2 mg - 400 mg
The finely ground active ingredient, part of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with starch residues and water into granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this, mixed and tablets of the appropriate size are pressed from this mixture.

B) Ampoule solutions
Active ingredient - 50 mg
Sodium Chloride - 50 mg
Aqua Injection - 5 ml
The active substance is dissolved at its own pH or, if necessary, at pH 5.5 to 6.5, in water and sodium chloride is added as an isotonant, the resulting solution is filtered in the absence of pyrogens and the filtrate under aseptic conditions is filled into ampoules, which are then sterilized and float. Ampoules contain 5 mg, 25 mg and 50 mg of the active substance.

Claims (8)

1. Derivatives of oxadiazole of the general formula (I)

in which X and Y mean oxygen or nitrogen, and X and Y cannot be simultaneously oxygen or nitrogen;
Z is a radical of the formula

in which S ¹ and S ² mean radicals of the formula

in which V means oxygen, sulfur;
B and D mean identical or different C ₁ -C ₁₀ alkylene bridges which may be substituted once or repeatedly by substituents such as = O, 1,3-dioxolane or 1,3-dioxane;
S ¹ and S ² mean radicals of the formula

in which V and B have the above meanings;
and U is a C ₃ -C ₆ cycloalkyl group or a C ₆ -C ₁₀ aryl group, which respectively can be substituted once or repeatedly by C ₁ -C ₄ alkyl, —NR ⁵ R ⁶ ;
S ¹ and S ² mean radicals of the formula

in which B and D have the above meanings and both groups D and both radicals R ⁴ may be the same or different;
S ¹ and S ² mean radicals of the formula

wherein V and D have the above meanings;
S ¹ and S ² mean radicals of the formula

wherein V and U have the above meanings;
S ¹ and S ² mean radicals of the formula

moreover, D has the above meanings and both groups D and both radicals R ⁴ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which E means NR ⁷ (n, m = 2 or 3 and n + m>2);
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings and W means a radical of the formula

optionally substituted with C ₁ -C ₄ alkyl, in which E is NR ⁷ and n, m, l = 0, 1 or 2, or W is a 5, 6-membered heterocycle connected via a carbon atom containing one or more heteroatoms from the series nitrogen, oxygen, which, if necessary, may be substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ and S ² mean radicals of the formula
-VW,
in which V and W have the above meanings;
S ¹ and S ² mean radicals of the formula

in which B has the above meanings and both substituents R ⁷ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which both substituents R ⁷ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which B, V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which B and D have the above meanings and both groups D and both substituents R ⁴ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which D has the above meanings and both groups D and both substituents R ⁴ may be the same or different;
Q means a condensed, once unsaturated 5-membered ring, which may contain one or more heteroatoms from the series oxygen;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical which, if necessary, is substituted directly or via alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C ₁ -C ₄ alkyl, -CF ₃ , —NR ⁵ R ⁶ , —NO ₂ , —OR ⁷ or a substituent of the formula

in which B, V or D have the above meanings;
R ¹ means phenyl, which is substituted by a substituent of the formula

in which B, V, U have the above meanings;
R ¹ means phenyl, which is substituted by a substituent of the formula

in which V and D have the above meanings;
R ¹ means phenyl-C ₁ -C ₆ -alkyl, preferably phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₆ -alkenyl;
R ¹ means a radical of the formula M—, wherein M is a 5,6-membered heterocycle attached via a C- or N-atom which contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ means a C ₃ -C ₇ cycloalkyl radical,
R ¹ means, optionally substituted with C ₁ -C ₄ -alkyl, preferably methyl, norbornane, norbornene radicals, preferably adamantane or noradamantane radicals;
R ¹ means, if necessary, a substituted radical of the formula

R ² and R ^{3 are} the same or different radicals such as hydrogen, halogen, —OR ⁷ , C ₁ -C ₁₀ alkyl;
R ⁴ is an amine of the formula —NR ⁵ R ⁶ ;
R ⁴ means an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₁₀ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₁₀ -alkyl;
R ⁶ is C ₆ -C ₁₀ aryl, preferably phenyl;
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers or their mixtures, and also, if necessary, their pharmacologically safe salts with acids. 2. Derivatives of oxadiazole of the general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot both be oxygen or nitrogen at the same time,
Z is a radical of the formula

in which S ¹ and S ² mean radicals of the formula

in which V is oxygen, sulfur, B and D are the same or different C ₁ -C ₄ alkylene bridges which may be substituted with substituents such as = O;
S ¹ and S ² mean radicals of the formula

in which V and B are as defined above, a U is a C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₀ aryl group which may be substituted with substituents such as C ₁ -C ₄ alkyl, -NR ⁵ R ⁶ ;
S ¹ and S ² mean radicals of the formula

in which B and D have the above meanings and both groups D, as well as both radicals R ⁴ can be the same or different;
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings;
S ¹ and S ² mean radicals of the formula

in which V and U have the above meanings;
S ¹ and S ² mean radicals of the formula

in which D has the above meaning and both groups D, as well as both radicals R ⁴ can be the same or different;
S ¹ and S ² mean radicals of the formula

in which E means NR ⁷ (n, m = 2 or 3 and n + m>2);
S ¹ and S ² mean radicals of the formula

in which V and D have the above meanings, and W means a radical of the formula

optionally substituted with C ₁ -C ₄ alkyl in which E is NR ⁷ , n, m, l = 0, 1 or 2, or W is a 5.6-membered heterocycle attached via a carbon atom containing one or more heteroatoms from the series nitrogen, oxygen, which, if necessary, may be substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ and S ² mean radicals of the formula
-VW,
in which V and W have the above meanings;
S ¹ and S ² mean radicals of the formula

in which B has the above meanings and the substituents R ⁷ may be the same or different;
S ¹ and S ² mean radicals of the formula

in which the substituents R ⁷ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which B, V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which B and D have the above meanings and both groups D, as well as both substituents R ⁴ may be the same or different;
S ³ and S ⁴ mean radicals of the formula

in which V and D have the above meanings;
S ³ and S ⁴ mean radicals of the formula

in which D has the above meanings and both groups D, as well as both substituents R ⁴ may be the same or different;
Q means a condensed, once unsaturated 5-membered heterocycle containing one or more oxygen heteroatoms;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical, which, if necessary, is substituted once or repeatedly by one or more substituents, such as halogen, preferably fluorine, chlorine or bromine, a C ₁ -C ₄ alkyl radical, —CF ₃ , —NR ⁵ R ⁶ , —NO ₂ , —OR ⁷ , or one radical of the formula

in which B, V and D have the above meanings;
R ¹ means a phenyl radical which may be substituted with a substituent of the formula

in which B, V and U have the above meanings;
R ¹ means a phenyl radical which is substituted with a substituent of the formula

in which V and D have the above meanings;
R ¹ means phenyl-C ₁ -C ₄ -alkyl, preferably benzyl, phenyl-C ₂ -C ₄ -alkenyl;
R ¹ means a radical of the formula M—, wherein M is a 5 or 6 membered heterocycle attached via a C or N atom which contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ is C ₃ -C ₇ cycloalkyl, preferably cyclopropyl or cyclopentyl;
R ¹ means, optionally, substituted C ₁ -C ₄ alkyl, preferably methyl, norbornane, norbornene radicals, preferably adamantane or noradamantane radicals;
R ¹ means, if necessary, once or repeatedly substituted by a halogen, hydroxy group or methoxy group, a radical of the formula

R ² and R ^{3 are} the same or different radicals, such as hydrogen, hydroxy group, halogen, preferably fluorine, chlorine or bromine, C ₁ -C ₄ -alkyloxy group, preferably methyloxy, C ₁ -C ₄ -alkyl;
R ⁴ means —NR ⁵ R ⁶ ,
R ⁴ means an N-oxide with the formula

R ⁵ means hydrogen, C ₁ -C ₄ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₄ -alkyl;
R ⁶ means a phenyl radical;
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids. 3. Oxadiazole derivatives of the general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot be oxygen or nitrogen at the same time; Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur and B and D are the same or different C ₁ -C ₄ alkylene bridges which may be substituted with substituents such as = O;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means a radical of the formula

in which V has the above meanings and U is C ₃ -C ₆ cycloalkyl or phenyl groups which may be substituted with C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula

in which B and D have the above meanings and both groups D as well as both substituents R ^{4 are the} same or different;
S ¹ means a radical of the formula

in which D has the above meanings and both groups D, as well as both substituents R ^{4 are the} same or different;
S ¹ means a radical of the formula

in which E means NR ⁷ (n, m = 2 or 3 and n + m>2);
S ¹ means a radical of the formula

in which V and D have the above meanings, and W means a radical of the formula

optionally substituted with C ₁ -C ₄ alkyl, in which E is NR ⁷ , n, m, l = 0, 1 or 2, or W is a 5- or 6-membered heterocycle attached via a carbon atom that contains one or more heteroatoms from the series nitrogen, oxygen, and which, if necessary, is substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
S ² means a radical of the formula

in which V and D have the above meanings;
S ⁴ means a radical of the formula

in which V and D have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle containing one or more oxygen heteroatoms;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a benzyl or phenyl radical, the latter can be singly or repeatedly substituted with one or more substituents, such as fluorine, chlorine or bromine, —C ₁ -C ₄ alkyl, —CF ₃ , —NMe ₂ , —NET ₂ , -NO ₂ or -OR ⁷ ;
R ¹ means a phenyl radical substituted with a radical of the formula

in which V is oxygen and D is a C ₁ -C ₄ alkyl bridge;
R ¹ means a 5- or 6-membered heterocycle attached via a carbon or nitrogen atom that contains one heteroatom from the series nitrogen, oxygen or sulfur;
R ¹ means cyclopropyl, cyclopentyl or cyclohexyl;
R ¹ means norbornane, norbornene, adamantane or noradamantane, optionally substituted with a methyl group;
R ¹ means a radical of the formula

R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁴ means an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
R ⁷ means hydrogen, C ₁ -C ₄ -alkyl,
if necessary, in the form of their racemates, their enantiomers, in the form of stereomers or their mixtures, and also, if necessary, their pharmacologically safe salts with acids. 4. Compounds of general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot both be oxygen or nitrogen at the same time; Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur, B is —CH ₂ - and D is one of the —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ —CH ₂ -, —CH ₂ —C ( CH ₃ ) H-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings, and W means a radical of the formula

optionally substituted with a C ₁ -C ₄ alkyl group or
W is a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which is optionally substituted with benzyl or C ₁ -C ₄ alkyl;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
S ² means a radical of the formula
- (CH ₂ ) _0,1 -O- (CH ₂ ) _2,3 -R ⁴ ,
Q means a condensed, once unsaturated 5-membered ring, which may contain one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means radicals, cyclopropyl, cyclopentyl, benzyl or phenyl, the latter can be singly or repeatedly substituted with one or more substituents, such as fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl, -CF ₃ , -NMe ₂ , -NO ₂ or -OR ⁷ ;
R ¹ means phenyl substituted by a radical of the formula
-O- (CH ₂ ) _2,3 -R ⁴ ,
R ¹ means furan, thiophene, pyridine or pyrrole;
R ¹ means norbornane, norbornene, adamantane or noradamantane;
R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
R ⁷ means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids. 5. The compounds of general formula (I) according to claim 1, wherein X and Y are nitrogen or oxygen, wherein X and Y cannot be simultaneously oxygen or nitrogen, Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur, B is —CH ₂ - and D is one of the —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ —CH ₂ -, —CH ₂ —C ( CH ₃ ) H-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-;
S ¹ means a radical of the formula

in which V and D have the above meanings;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings and W means a radical with the formula

optionally substituted with a C ₁ -C ₄ -alkyl group, or W means a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which may be optionally substituted with benzyl or C ₁ -C ₄ -alkyl;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle that contains one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means cyclopropyl, cyclopentyl or phenyl radicals, wherein the phenyl ring can be substituted once or repeatedly by one or more substituents, such as fluorine, chlorine, bromine, C ₁ -C ₄ alkyl radical, -CF ₃ , -NMe ₂ , -NO ₂ or -OR ⁷ ;
R ¹ means furan, thiophene, pyridine or pyrrole;
R ¹ means norbornane, norbornene, adamantane or noradamantane;
R ¹ is —CH = CH-phenyl;
R ² is hydrogen, fluoro, chloro, bromo, a C ₁ -C ₄ alkyloxy group, a C ₁ -C ₄ alkyl or hydroxy group;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

R ⁵ means hydrogen, C ₁ -C ₃ -alkyl;
R ⁶ means hydrogen, C ₁ -C ₃ -alkyl, benzyl or phenyl;
R ⁷ means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, as well as, if necessary, their pharmacologically safe salts with acids. 6. The compounds of general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot both be oxygen or nitrogen at the same time; Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen, sulfur and D is one of the groups —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ —CH ₂ -, —CH ₂ —C (CH ₃ ) H—, - CH ₂ —CO—, —CH ₂ —CH ₂ —CO—;
S ¹ means piperazin-1-yl, 4-methylpiperazin-1-yl radicals;
S ¹ means a radical of the formula

in which V and D have the above meanings and W means a radical of the formula

or W means a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, which is optionally substituted with a methyl group;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle that contains one oxygen heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical, which, if necessary, once or repeatedly substituted by one or more substituents such as fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF ₃ or - OR ⁷ ;
R ¹ means furan, thiophene or pyridine;
R ² is hydrogen, fluoro, chloro, bromo, methyl, methyloxy or hydroxy;
R ³ means hydrogen;
R ⁴ means —NR ⁵ R ⁶ or an N-oxide of the formula

R ⁵ means hydrogen, methyl, ethyl, n-propyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;
R ⁷ means hydrogen, methyl or ethyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if necessary, their pharmacologically safe salts with acids. 7. The compounds of general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot be oxygen or nitrogen at the same time; Z is a radical of the formula

in which S ¹ means a radical of the formula

in which V is oxygen and D is one of the groups —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ —C (CH ₃ ) H—, —CH ₂ —CH ₂ —CO—;
S ¹ means the radicals of N-piperazinyl;
S ¹ means a radical of the formula

in which V and D have the above meanings, and W means a radical of the formula

or W is a 5- or 6-membered heterocycle attached via a carbon atom containing nitrogen, optionally substituted with a methyl group;
S ¹ means a radical of the formula
-VW,
in which V and W have the above meanings;
Q means a condensed, once unsaturated 5-membered heterocycle containing oxygen as a heteroatom;
S ⁵ means a radical of the formula
-DR ⁴ ,
in which D has the above meanings;
R ¹ means a phenyl radical which may be substituted once or repeatedly by one or more substituents, such as fluorine, chlorine, bromine, methyl radical, —CF ₃ , hydroxy group, methyloxy group or ethyloxy group;
R ¹ means furan, thiophene or pyridine;
R ² means hydrogen, fluorine, chlorine or methyl;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁵ means hydrogen, methyl, ethyl, n-propyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if necessary, their pharmacologically safe salts with acids. 8. The compounds of general formula (I) according to claim 1, wherein X and Y are oxygen or nitrogen, wherein X and Y cannot be oxygen or nitrogen at the same time; Z is a radical of the formula

in which S ¹ means one of the radicals —O — CH ₂ —CH ₂ —R ⁴ , —O — CH ₂ —C (CH ₃ ) HR ⁴ , —OC (CH ₃ ) H — CH ₂ —R ^4, or —CH ₂ -CH ₂ -CO-R ⁴ ;
S ¹ means one of the radicals —O — CH ₂ —W or —OW, in which W is a 5- or 6-membered heterocycle attached via a carbon atom, including a nitrogen atom, which is optionally substituted with a methyl group;
Q means a condensed, once 5-membered heterocycle containing oxygen as a heteroatom;
S ⁵ means a radical of the formula —CH — R ⁴ ;
R ¹ means a phenyl radical which may be substituted once or repeatedly by one or more substituents, such as fluorine, chlorine, bromine, methyl, —CF ₃ , hydroxy, methyloxy or ethyloxy;
R ¹ means thiophene;
R ² means hydrogen, fluorine, chlorine or methyl;
R ³ means hydrogen;
R ⁴ is —NR ⁵ R ⁶ ;
R ⁵ means hydrogen, methyl, ethyl, isopropyl;
R ⁶ means hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl,
if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers or their mixtures, if necessary, their pharmacologically safe salts with acids.

Images